Human mycoses can be largely classified into cutaneous mycoses and systemic mycoses and the latter is more of concern. Despite the advancement in medical technologies during the past 20 years, the systemic mycoses are on the increase. The mycoses occur frequently in patients whose immune functions have been weakened due to excessive use of antibacterial agents, organ transplantations, long-term medication of anti-cancer medicines, aging, and AIDS, etc., or in patients who rely on catheters or prosthetic devices (Beck-Sague, C. M. et al. J. Infect. Dis., 167, 1247-1251, 1993; Diamond, R. D., Rev. Infect. Dis., 13, 480-486, 1991). Moreover, according to a report, about 40% of the patients who are hospitalized with infection die of mycoses, with the representative opportunistic pathogens being Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, etc. (Strenberg, S., Science, 266, 1632-1634, 1994).
The occurrence of invasive candidiasis has increased by ten-fold. The invasive aspergillosis, which frequently occurs in lungs, is the primary cause of death for the bone marrow-transplanted patients (Pannuti, C. et al., Cancer, 69, 2653-2662, 1992) and the death caused by aspergillosis is on the increase. Thus, the necessity of a new antifungal agent is ever increasing. Since most of the mycoses caused by opportunistic infection are hard to diagnose with the common blood culture, even the treatment of severe immunodeficiency patients is performed depending only on experiences (Walsh, T. J. et al., Rev. Infect. Dis., 13, 496-503, 1991). Most mycoses have been known to occur mainly in patients with weakened immune functions. But, since the earthquake that outbroke in 1994 around Los Angeles (LA), hundreds of mycoses cases had occurred for 3 consecutive years as the spores that had been buried in earth were scattered into the air. During this period, the mortality increased by more than ten times, and with this incidence, it was reported that the fear of mycoses was no longer confined to the patients with weakened immune functions (Strenberg, S., Science, 266, 1632-1634, 1994). The increase of mycoses is gaining the attentions of researchers, yet the prevention of the conditions is not an easy task. In particular, due to the lack of an antifungal agent having superior efficiency with little toxicity, the amphotericin B, which was developed in the 1960s, is still being used in clinical treatment of systemic mycoses in spite of its high toxicity (Georgopadakou, N. H. et al., Science, 264, 371-373, 1994). Moreover, the occurrence of fungal strains resistant to existing antifungal agents is on the increase (Rex, J. H. et al., Antimicrob. Agents Chemother., 39, 1-8, 1995).
Also, the number of cases where a non-pathogenic strain turns into pathogenic strain in patients with weakened immune functions is increasing. Since pathogenic fungi are hard to culture and mostly reproduce asexually, systematic researches on pathogenic fungi have long been deferred (Strenberg, S., Science, 266, 1632-1634, 1994).
At present, the antifungal agents used for clinical purposes are mostly polyenes, azole derivatives, allylamines and thiocarbamates. They either interact with ergosterol, the cell membrane component of fungi, or inhibit the synthesis of ergosterol. However, since most of the compounds have fungistatic activity and the fungi resistant to them appear very frequently, the development of new antifungal agents has been on constant demand. For the treatment of systemic fungal infections, amphotericin B is still widely used because of the lack of superior medicines. However, since it is highly nephrotoxic and may induce pernicious anemia when administered repeatedly, preparation forms developed using lipid complex, colloidal dispersion and liposome to reduce the toxicity were also reported (Kauffman, C. A. et al., Drugs, 53, 539-549, 1997).
Since fungi have cell walls that are different from those of mammals, the cell wall of fungi has long been seen as a good target. The cell wall of fungi maintains the cell structure, prevents the cell from being destroyed by osmosis while participating in the transfer of macromolecules. The cell wall of fungi is made up of chitin, α-glucan, β-glucan, mannan, etc. Of these, chitin, or β-1,3-glucan, has been the main target for the development of antifungal agents. Chitin is a homopolymer constructed from units of N-acetyl-d-glucosamine linked with β-1,4 glycoside bond. It is an essential component in the cell walls of almost all pathogenic fungi and the skeletal structures of in-vertebrates. Chitin is synthesized by chitin synthases 1, 2 and 3. Like Saccharomyces cerevisiae, Candida albicans harbours three chitin synthases 1, 2 and 3, which are analogous in terms of structure and function to those of Saccharomyces cerevisiae chitin synthases 2, 1 and 3, respectively. Chitin synthase 1 from Candida albicans participates in septum formation during cell division, while chitin synthase 3 participates in chitin ring formation during the formation of daughter cells from mother cells and the cell wall biogenesis. On the other hand, chitin synthase 2 recovers severely damaged cell wall during cell division (Mio T. et al., J. Bacteriol., 178, 2416-2419, 1996). Among them, chitin synthases 1 and 3 are the main targets for the development of new cell wall biogenesis inhibitors, as they are known as essential enzymes.
Berberine, the main component of Coptis chinensis Fr., which has been known as Huang Lian in Oriental medicine and has been used for the treatment for eye disease, diarrhea or inflammation, is gaining attention because of its antifungal activity. Many researches on berberine derivatives have been reported.

Particularly, berberine derivatives with a variety of functional groups substituted at the C-13 position have chitin synthase inhibitory effect and antifungal activity (Korean Patent No. 258849; Park K. S., et al., J. Antimicrob. Chemother., 47, 513, 2001).
The compound obtained by pyrolyzing berberine at high temperature to replace the methoxy group at the C-9 position with a hydroxyl group is called berberrubine. As shown below, the hydroxyl group at the C-9 position of berberrubine is present in the form of either a ketone group or a hydroxyl group and is reversibly transformed, as shown in the following formula:

Recently, a berberrubine derivative having improved antifungal activity or DNA-binding affinity by introducing an acyl or alkyl chain at the hydroxyl group of the C-9 position was reported (Kim S. H., Lee S. J., Lee J. Y., Sun W. S., Kim J. H., Planta Medica 03, 277(2002); Pang J. Y., Qin Y., Chen W. H., Luo G. A., Jiang Z. H., Bioorganic & Medicinal Chemistry 13, 5835(2005)). However, the introduction was restricted to the hydroxyl group at the C-9 position of berberrubine and a good antifungal activity was attained only when a hydrocarbon chain longer than 8 carbon atoms was introduced, yet it did not have chitin synthase inhibitory effect. Thus, the antifungal activity could be due to the destruction of cell membrane by the long hydrocarbon chain, and not due to the inhibition of chitin synthase. Such a long hydrocarbon chain renders the development difficult because of its intrinsic toxicity and low hydrophilicity as hydrocarbon.
Korean Patent No. 258,849 discloses that berberine derivatives in which various benzyl groups are introduced at the C-13 position or at the same time alkoxy groups are introduced at the C-9 and C-10 positions instead of two methoxy groups. In practice, only the berberine derivative represented by the following formula, wherein R1and R2 are —O—CH2—O— or OCH3, R3 is H, R4 is OCH3 and R5 is benzyl or substituted benzyl, is known to have antifungal activity.

However, according to the experiments carried out by the present inventors, the berberrubine derivatives of the present invention, in which methoxy is present at the C-10 position and a variety of C3-C10 alkoxy are substituted at the C-9 position, showed more potent antifungal activities than those of the substituted berberine derivatives of Korean Patent No. 258,849, in which identical substituents (methoxy) are substituted at the C-9 and C-10 positions (see Table 3 and Table 4 below). For the synthesis of the berberrubine derivatives introduced alkoxy groups at the C-9 position only, berberrubine used as a intermediate was synthesized by pyrolysis.